delta8-7-carbinoxy-steroid compounds and processes of preparing the same



United S t. tes Patent A8-7-CARBIN0XY-STER0ID COMPOUNDS AND PROCESSES FPREPARING THE SAME E Erickson, Cranford, NJ., assignor to Merci: & 'Co.,Inc., Rahway, NJ a corporation of New Jersey N0 Drawing. ApplicationDecember 31), 1955 Serial N0. 556,392

17 Claims. (c1. 260-23955 This invention is concerned generally withsteroid compounds having an ether group in the 7-position, a hydroxyl oracyloxy group in the ll-position, and an ethylenic un saturation betweenthe 8- and 9-positions, and with the processes for preparing thesecompounds. More particularly, it relates to a novel process forconverting A' -9,11- ep'oxy-cyclopentanopolyhydrophenanthrene compoundsto the corresponding A -7-C3Ibil1OXY1 l-(hydroxy or acyloxy)cyclopentanopolyhydrophenanthrene compounds and to these new conversionproducts as well. The A -7- carbinoxy-l l-(hydroxy oracyloxy)-cyclopentanopolyhydrophenanthrene compounds prepared inaccordance with my novel procedure are valuable as intermediates in thesynthesis of other steroid compounds such as the adrenal hormone,cortisone.

This application is a continuation-in-part of application Serial No.352,973, filed May 4, 1953, now abandoned.

The A -7-carbinoxy-1l-(hydroxy oracyloxy)-cyclopentanopolyhydrophenanthrene compounds, subject of thepresent invention, have at rings B and C the following chemicalstructure:

wherein R is a hydrocarbon radical, and R is a hydroxy or acyloxyradical.

These A -7-carbinoxy-11-(hydroxy oracyloxy)-cyclopentanopolyhydrophenanthrene compounds can be prepared asfollows: a A -9,11-epoxy+allo-cyclopentanopolyhydrophenanthrene compound(Compound 1 hereinbelow) is reacted with an alcohol in the presence of arelatively low concentration of an organic acid as catalyst, said acidhaving an ionization constant between 1.5 X l0 and 1.5 10- undersubstantially anhydrous conditions to form the corresponding A-7-carbinoxy-1l-hydroxyallo cyclopentanopolyhydrophenanthrene compound(Compound 2); the latter compound is converted by reaction with anacylating agent to the corresponding A -7 carbinoxy 11 acyloxy allocyclopentanopolyhydrophenanthrene compound (Compound 3).

The reactions indicated hereinabove may be chemically represented,insofar as rings B and C are concerned as follows:

H0- R20 O r I Alcohol l Acylating I organic O R agent R d ca t iystCompound 1 Compound 2 Compound 3 ice 2 wherein R is an acyl radical andR has the significance above defined. I

The A' -9, 1 1-epoxy-allo-cyclopentanopolyhydroplierian: threnecompounds which I ordinarily employ as starting materials in carryingout the presently invented process are those having a sterol side chainattached to the carbon atom in the 17-position of the molecule such asergosteryl D-acetate epoxide, A -9,ll-epoxy-ergostadiene', A'-3-acyloXy-9Jl-epoxy-ergostadiene, 13 9,11- epoxy-cholestene', A-3-acyloxy-9,1l-epoxy-cholestene, A 3 acetoxy 9,11 epoxy cholestene, A 3acyloxy 9,11 epoxy sti'gmastadiene, A 3 acetoxy 9,11epoxy-stigmastadiene, a bile acid side chain attached to the 17-carbonatom such as A -3-acyloxy-9,1l-epoxy-allocholenic acid, A'-3-acetoXy-9,1l-epoxy-allocholenic acid, and alkyl esters thereof, adegraded bile acid side chain attached to the 17-carbon atom such asA"-3-acyloxy-9,11- epoxy-bisnor-allocholenic acid,A"-3-acetoxy-9,ll-epoxybisnor-allocholenic acid, and alkyl estersthereof, a 17- acetyl substituent such as A -3-acyloxy-9,l1-ep0xy-2Oketo-allopregnene, A' -3-acetoXy-9,1 l-epoxy-ZO-keto-allopregnene, asapogenin side chain such as A -9,11-epo-xydehydrotigogenin acylate, A-3-acetoxy-9,1l-epoxy-dehydrotigogenin, and the like.

These A' -9, 1 1-epoxy-allo-cyclopentanopolyhydrophen- 'anthrenecompounds, utilized as starting materials in my process are convenientlyprepared in accordance with procedures described in J.A.C.S. 73, 2396(1951). I ordinarily start with readily available A-cyclopentanopolyhydrophenanthrene compounds such as ergosterol-D and3-acyloxy derivatives thereof; other A-allo-cyclopentanopolyhydrophenanthrene compounds are also easilyprepared, starting with readily available A-cyclopentanopolyhydrophenanthrene compounds such as cholesterol, bytreating said .A -cyclopentanopolyhydrophenanthrene compound WithN-bromosuccinimide, reacting the resulting A-7-bromo-cyclopentanopolyhydrophenanthrene compound With a tertiaryamine to form the corresponding A -cyclopentanopolyhydrophenanthrenecompound, reacting this compound with hydrogen in the presence of Raneynickel catalyst thereby selectively reducing the unsaturated linkageattached to the carbon atom in the 5- position to form the correspondingA -cyclopentanopolyhydrophenanthrene compound and bringing said A'cyclopentanopolyhydrophenanthrene compound into intimate contact with asolution of mercuric acetate in acetic acid thereby producing thecorresponding A -cyclopentanopolyhydrophenanthrene compound. The Acyclopentanopolyhydrophenanthrene compound is then converted to thecorresponding epoXide by reaction with perbanzoic acid thus forming thecorresponding .A -9,11- epoxy cyclopentanopolyhydrophenanthrene compound(Compound 1 hereinabove).

In carrying out my novel process, theA"-9,11-epoxyallocyclopentanopolyhydrophenanthrene compound, utilized asstarting material therein, is reacted with an alcohol in the presence ofa relatively low concentration of an organic acid as catalyst, said acidhaving an ionization constant between 1.5 l0 and 1.5 10- undersubstantially anhydrous conditions to produce the corresponding A 7carbinoxy-l1-hydroxy-cyclopentanopolyhydrophenanthrene compound.Suitable alcohols for the reaction are the aliphatic cycloaliphatic, andarylaliphatic alcohols such as methyl alcohol, ethyl alcohol,cyclohexanol, benzyl alcohol, and the like. The amount of organic acidcatalyst used is usually less than about 1% by volume of the reactionmixture and within the range of 0.1 and 0.3% by volume of the reactionmixture. While formic acid is the preferred catalyst, monochloraceticacid is almost as effective. Acids having an ionization constant greaterthan 1.5 10- tend to promote the further rearrangement to unsaturatedketones. Acids having ionization constants lower than 1.5 1O- act muchslower and greatly increase the reaction time, e.g., glacial acetic acidtakes about twenty-four hours to catalyze the reaction in comparisonwith from 1 to 6 hours for formic and mono-. chloracetic acids.

The reaction mixture should be maintained essentially anhydrous, sincewater may cause cleavage of the ether to a hydroxyl group. However,traces of moisture do not appear to harm the reaction and 88% formicacid is ordinarily employed rather than the anhydrous acid; when 88%formic acid is utilized as catalyst in an amount equal to about 1% byvolume of the reaction mixture, the quantity of water in the resultingmixture is only about 0.1% of said mixture. It is also advantageous tocarry out the reaction in an inert atmosphere to avoid oxidation of thehydroxy compounds formed, but this is not essential to the success ofthe reaction.

The process is preferably carried out at the reflux temperature of thealcohol which also functions as the solvent medium. With the loweralkanols which are preferred, the temperature is therefore in the rangeof about 60-80 C., but still higher temperatures may be employed sincethe monoether is quite stable in the absence of water.

Hydroxyl groups at the 3-position in the starting compounds are notattacked during the reaction, but are usually esterified prior toreaction in order to facilitate the further operations on the7-carbinoxy-l1-hydroxy compound. Acylation at the 3-position prior toreaction is much more desirable than any subsequent selectivemonoacylation of the 3,11-diol which would be formed.

, The desired end product may be isolated and purified by conventionalmethods such as removal of the alcoholic solvent, chromatography, andrecrystallization.

The reaction between the epoxide of the E-allocyclopentanopolyhydrophenanthrene compound and the alcohol resultsin the formation of the corresponding A 7carbinoxy-11-hydroxy-cyclopentanopolyhydrophenanthrene compound such asA -7-methoxy-1l-hydroxyergostadiene, A 7 ethoxy 11 hydroxy ergostadiene,A 7 cyclohexyloxy 11 hydroxy ergostadiene, A 7 benzyloxy 11 hydroxyergostadiene, A 3 acyloxy 7 methoxy 11 hydroxy ergostadiene, A 3 acyloxy7 ethoxy 11 hydroxy ergosta menial/1 3 acyloxy 7 cyclohexyloxy 11 hydroxy ergostadidne, A 3 acyloxy 7 benzoyloxy 11 hydroxy ergostadidne, A3 acetoxy 7 meth oxy ll hydroxy ergostadiene, A 3 acetoxy 7 ethoxy llhydroxy ergostadidne, A 3 acetoxy 7 cyclohexyloxy 11 hydroxyergostadidne, A 3 acetoxy 7 benzyloxy 11 hydroxy ergostadidine, A 7methoxy 11 hydroxy cholestene, A 7 ethoxy 11 hydroxy cholestene, A 7cyclohexyl oxy l1 hydroxycholestene, A 7 benzyloxy 11 hydroxycholestene, A 3 acyloxy 7 methoxy 11 hydroxy cholestene, A 3 acyloxy 7ethoxy 11 hydroxy cholestene, A 3 acyloxy 7 7 cyclohexyloxy ll hydroxycholestene, A 3 acyloxy 7 benzyloxy 11 hydroxy cholestene, A 3 acetoxy 7methoxy 11 hydroxy cholestene, A 3 acetoxy 7 ethoxy l1 7 hydroxycholestene, A 3 acetoxy 7 cyclo hexyloxy 11 hydroxy cholestene, A 3acetoxy 7 benzyloxy 11 hydroxy cholestene, A 3 acyloxy 7 methoxy 11hydroxy stigmastadidne, A 3 acyloxy ethoxy 11 hydroxy stigmastadiene, A3 acyloxy 7 cyclohexyloxy 11 hydroxy stigmasta diene, A 3 acyloxy 7benzyloxy 11 hydroxy stigmastadiene, A 3 acetoxy 7 methoxy 11 hydroxystigmastadiene, A 3 acetoxy 7 ethoxy 11 hydroxy stigmastadiene, A8122 3acetoxy 7 cyclohexyloxy 11 hydroxy stigmastadiene, A8122 3 acetoxy 7benzyloxy 11 hydroxy stigmastadiene, A 3 acyloxy 7'- methoxy 11 hydroxybisnoral locholenic acid, A 3 acyloxy 7 ethoxy ll hy droxybisnorallocholenic acid, A 3 acyloxy 7 cyclohexyloxy 11 hydroxy'bisnorallocholenic acid, A3-acyloxy-7-benzyloxy-11hydroxybisnorallocholenic acid, A 3 acetoxy 7methoxy 11 hydroxy bisnorallo cholenic acid, A 3 acetoxy 7 ethoxy 11hydroxy bisnorallocholenic acid, A 3 acetoxy 7 cyclohexyl oxy 11 hydroxybisnorallocholenic acid, A 3 acetoxy 7 benzyloxy 11 hydroxybisnorallocholenic acid, A 3 acyloxy 7 methoxy 11 hydroxy 20 ketoallopregnene, A 3 acyloxy 7 ethoxy 11 hydroxy 20 keto allopregnene, A 3-acyloxy 7 cyclohexyloxy 11 hydroxy 20 keto allopregnene', A 3 acyloxy 7benzyloxy 11 hydroxy 20 keto allopregnene, A 3 acetoxy 7 methoxy 11hydroxy 20 keto allopregnene, A 3 acetoxy 7 ethoxy 11 hydroxy 20 ketoallopregnene, A 3 acetoxy 7 cyclohexyloxy 11 hydroxy 20 ketoallopregnene, A 3 acetoxy 7 benzyloxy 11 hy droxy 20 keto allopregnene,A 7 methoxy 11- hydroxy dehydrotigogenin acylate, A 7 ethoxy 11 hydroxydehydrotigogenin acylate, A 7 cyclohexyl oxy 11 hydroxy dehydrotigogeninacylate, A 7- benzyloxy 11 hydroxy dehydrotigogenin acylate, A methoxy11 hydroxy dehydrotigogenin acetate, A 7 cyclohexyloxy 11 hydroxydehydrotigogenin acetate, A 7 benzyloxy 11 hydroxy dehydro tigogeninacetate, and the like. These compounds may be reacted with an acyl'atingagent, as for example, a lower alkanoic acid anhydride such as aceticpropionic or butyric anhydride to form the corresponding A 7 carbinoxy11 acyloxy allo cyclopentanopolyhydrophenanthrene compound. The A-7-carbinoxy-1l-hydroxy cyclopentanopolyhydrophenanthrene compounds, forexample, A N-acetoxy-7-methoxy-1l-hydroxy-ergostadiene, or A-7-methoxy-1l-hydroxy-dehydrotigogenin 3-acetate is reacted withchromium trioxide-acetic acid thereby forming the corresponding A-7-carbinoxy-11-keto-cyclopentanopolyhydro phenanthrene compound (e.g.,11 -3-acetoxy-7-methoxy ll-keto-ergostadiene or A-7-methoxy-1l-keto-dehydrotigogenin B-acetate); the latter compound isdissolved in acetic acid and the resulting solution reacted with hydrogen in the presence of platinum catalyst, thereby cleaving theallylic ether linkage and saturating the A double bond to produce thecorresponding ll-keto-cyclopentanopolyhydrophenanthrene compound (e.g.,A -3- acetoxy-ll-keto-ergostene or ll-keto-dehydrotigogenin 3- acetate).These ll-keto steroids are converted to adrenal hormones such ascortisone acetate in accordance with the procedures set forth inJ.A.C.S. 73, 2396 (1951); J.A.C.S. 73, 4052 (1951); and Nature 168, 28(1951).

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 A solution of 20 g. of ergosterol-D epoxide in 2 liters ofmethanol and 2 cc. of formic acid Was heated at reflux temperature fortwo hours in a nitrogen atmosphere. The solution was then concentratedto dryness in vacuo, and the rmidue dissolved in 200 cc. of ether. Theethereal solution was washed with Water, dried over sodium sulfate, andconcentrated in vacuo to dryness. The crude diol monoether thus obtainedwas chromatographed on acid-washed alumina, and the product obtainedfrom the acetone-ether eluate recrystallized from acetone. The purified11 -3;1-dihydroxy-7-methoxy-ergostadiene thus obtained melted at 154-155C., [u] (CHCl Analysis.Calcd for C I-1 0 C, 78.30; H, 10.88. Found: C,78.66; H, 11.11.

Example 2 A solution of 1.29 g. of n3,11-dihydroxy-7-methoxy-ergostadiene in 3 cc. of pyridine and 3 cc. ofacetic anhydride was allowed to stand at room temperature overnight.Three hundred cubic centimeters of ice water was then added withstirring to the solution. The formed solid was filtered, washed free ofacid with water, and dried in vacuo. On recrystallization from methanolthere was obtained A -3,11-diacetoxy-7-methoxy-ergostadiene, M.P.l34.5135.5 C. Analysis.-Calcd. for C H O C, 74.96; H, 9.91. Found: C,75.17; H, 9.56.

Example 3 A solution of 3 g. of ergosterol-D acetate epoxide in 300 cc.of methanol containing 0.3 cc. of formic acid was heated, undernitrogen, at reflux temperature for two hours. The reaction mixture wasthen concentrated to a volume of about 50 cc., and 300 cc. of ice wateradded. The crude solid was filtered, washed free of acid and dried. Thecrude product so obtained was chromatographed on acid-washed alumina.The residue from the acetone-ether eluate was recrystallized frommethanol to yield A -3-acetoxy-7-methoXy-1l-hydroxy-ergostadiene, M.P.159-160 C., [u] =|-57 (CHCl Various changes and modifications may bemade in carrying out the present invention without departing from thespirit and scope thereof. Insofar as these changes and modifications arewithin the purview of the annexed claims, they are to be considered aspair of my invention.

I claim:

1. A A -allosteroid having the following formula:

wherein Y is a lower hydrocarbon radical, Z is a radical selected fromthe group consisting of hydrogen and lower hydrocarbon carbonylradicals, X is a radical selected from the group consisting of hydroxyand keto radicals, and R is an organic side chain selected from thegroup which consists of ergosterol side chain, cholesterol side chain,stigmasterol side chain, cholanic acid side chain, bisnorcholanic acidside chain, pregnane side chain, and tigogenin side chain.

2. A -7-lower alkoxy-3,1l-dihydroxy-ergostadiene.

3. A -7-lower alkoxy 3,11 bis(lower a1kanoyloxy)- ergostadiene.

4. M -3,11-dihydroXy-7methoxy-ergostadiene.

5. 11 -3-acetoxy-7-methoxy-1l-hydroxy-ergostadiene.

6. A -3,11-diacetoXy-7-methoxy-ergostadiene.

7. A -7-lower alkoXy-3,11-dihydroxy dehydrotigogenin.

8. A -7-lower alkoXy-3,11-bis(lower alkanoyloxy) dehydrotigogenin.

9. A -3-acetoxy 7 methoxy-l l-hydroxy dehydrotigogenin.

10. A -3,1l-diacetoXy-7-methoXy-dehydrotig0genin.

11. The process which comprises reacting a carbinol, in the presence ofan organic acid catalyst, with a A"- allosteroid having the followingformula:

wherein Z is a radical selected from the group which consists ofhydrogen and lower hydrocarbon carbonyl radicals, and R is an organicside chain selected from the group which consists of ergosterol sidechain, cholesterol side chain, stigmasterol side chain, cholanic acidside chain, bisnorcholanic acid side chain, pregnane side chain, andtigogenin side chain; thereby producing a A -allosteroid of the formula:

wherein Y is a lower hydrocarbon radical, and R has the significanceabove-defined.

12. The process which comprises reacting A7122 3- (lower alkanoyloxy)9,11-epoXy-ergostadiene with an alkanol in the presence of an organicacid catalyst thereby producing A -3-(lower alkanoyloxy) 7-loweralkoxy-llhydroXy-ergostadiene compound.

13. The process which comprises reacting ergosterol-D acetate cpoxidewith methanol in the presence of formic acid catalyst to produce 11-3-acetoxy-7-methoXy-11- hydroxy-ergostadiene.

14. The process which comprises reacting ergosterol-D epoxide with alower alkanol in the presence of from about .1% to about .3% by volumeof formic acid under substantially anhydrous conditions to produce thecorresponding N -3,11-dihydroXy-7-lower alkoxy ergostadiene.

15. The process which comprises treating a methanolic solution ofergosterol-D epoxide with from about .1% to about .3% by volume offormic acid under substantially anhydrous conditions, separating the A-3,11-dihydroxy- 7-methoxy-ergostadiene which is formed, and subjectingit to acylation to form A -3,11-diacet0xy-7-methoxyergostadiene.

16. The process which comprises reacting A' -3-(lower alkanoyloxy)-9,1l-epoxy-dehydrotigogenin with an alkanol in the presence of anorganic acid catalyst thereby producing A -3(lOW6I alkanoyloxy) 7-1oweralkoxy-llhydroxy-dehydrotigogenin compound.

17. The process which comprises reacting ergosterol-D epoXide withmethanol in the presence of from about .1% to about .3% by volume offormic acid under substantially anhydrous conditions to produce A-3,11-dihydroxy-7-methoxy-ergostadiene.

Fieser & Fieser, Natural Compounds Related to Phenanthrene, page 425,3rd edition, 1949.

1. A $8-ALLOSTEROID HAVING THE FOLLOWING FORMULA: